The innate immune system is the first line of defense which is initiated by pattern recognition receptors (PRRs) upon detection of ligands from pathogens as well as damage associated molecular patterns. A growing number of these receptors have been identified, which now includes sensors of double stranded DNA and unique nucleic acids called cyclic dinucleotides (CDNs). Activation of PRRs leads to up regulation of genes involved in the inflammatory response, including type 1 interferons (IFNs), proinflammatory cytokines and chemokines which suppress pathogen replication and facilitate adaptive immunity.
The adaptor protein STING, also know as TMEM 173, has been identified as a central signalling molecule in the innate immune sensing pathway in response to cytosolic nucleic acids. Activation of STING results in up-regulation of IRF3 and NFκB pathways leading to induction of INF-β and other cytokines. STING is critical for responses to cytosolic DNA from pathogens or of host origin, and in response to CDNs, sometime referred to second messengers. G. N. Barber, “Sting: infection, inflammation and cancer,” Nat. Rev. Immun., 2015, 15, pp 760.
CDNs were first identified as bacterial messengers responsible for controlling numerous responses in prokaryotic cells. Bacterial CDNs, such as c-di-GMP are symmetrical molecules characterized by two 3′,5′ phosphodiester linkages. Direct activation of STING by bacterial CDNs has recently been confirmed through X-ray crystallography. Bacterial CDNs have consequently attracted interest as potential vaccine adjuvants.
More recently, the response to cytosolic DNA has been shown to involve generation of endogenous CDNs by an enzyme called cyclic guanine adenine synthase (cGAS), producing a novel mammalian CDN signalling molecule identified as cyclic guanine adenine monophosphate (cGAMP), which binds to and activates STING. Interaction of cGAMP with STING has also been demonstrated by X-ray crystallography. Unlike bacterial CDNs, cGAMP is an unsymmetrical molecule characterised by its mixed 2′,5′ and 3′,5′ phosphodiester linkages. Like bacterial CDNs, cGAMP activates STING leading to induction of type 1 INFs:

The role of type 1 INFs in response to invading pathogens is well established. Recombinant IFNα was the first approved biological therapeutic and has become an important therapy in viral infections and in cancer. INFs are also know to be potent modulators of the immune response, acting on cells of the immune system.
Given its role in regulating various biological processes, STING is an attractive target for modulation with small molecules. Nevertheless, to date, few effective STING activators have been developed or have entered the clinic.